Excitability of cells and tissues is an essential physiological function that allows organisms to sense their environment and respond to it. The primary goal of this work is to explain key physical-chemical features of cell and tissue excitability, many aspects of which are still poorly understood. Widely accepted theories of nerve excitability do not explain several anomalous phenomena that we have shown are necessary for excitation to occur. These include reversible volume, temperature, and optical changes of the superficial protoplasmic layer of nerve axons, which coincide with the arrival of the action potential waveform. We have obtained further evidence that these physical changes accompany a phase transition that occurs in nerve cells, fibers, and synapses caused by the exchange of divalent cations like calcium with monovalent cations like sodium and potassium. Our previous experiments with perfused axons clearly implicate divalent/monovalent cation exchange as a mechanism by which nerve fibers can be excited in an "all or none" manner. To understand the physical chemical basis of these temperature and volumetric changes, particularly how divalent/monovalent cation exchange can induce such changes in biomolecular assemblies, we are studying these processes in synthetic "biomimetic" anionic polymer gels under nearly physiological conditions. An advantage of studying the behavior of these gel model systems is that their structure, composition, and the interactions among their components can be carefully controlled, unlike in living tissue. In particular, in synthetic polyacrylate gels, Ferenc Horkay has observed that minute changes in the concentration of divalent cations in the surrounding liquid can induce significant changes in chain stiffness in the gel, even if ion binding is weak and completely reversible. Various physical chemical and polymer physics-based techniques, including neutron, x-ray and light scattering, as well as osmotic swelling, and mechanical loading provide complementary information with which to study these biologically relevant phenomena over a wide range of length scales. These basic studies are leading to a deeper understanding of the physical mechanisms underlying nerve excitation. We are also investigating biophysical aspects of stimulation by electromagnetic induction (magnetic stimulation) in the central and peripheral nervous systems. Pedro Miranda has performed detailed calculations using a finite element method (FEM), to predict the electric field and current density distributions induced in the brain during magnetic stimulation. Previously, we found that both tissue heterogeneity and anisotropy of the electrical conductivity contribute significantly to distort the induced fields, and even to create excitatory or inhibitory "hot spots" in some regions. These phenomena could have significant clinical consequences both in interpreting or inferring the region or locus of excitation and in determining the source of nerve excitation. More recently, we have focussed on possible physical mechanisms of cortical excitation. Longterm goals are to marry our macroscopic models of magnetic stimulation in nerve tissue with microscopic models of nerve excitability in the CNS and PNS.